Motivational abnormalities are core deficits in several mental disorders including schizophrenia, depression, and drug addiction. To develop more effective therapeutic strategies for these deficits the underlying molecular mechanisms and the relevant changes in neuronal function and circuitry have to be identified. The long-term goal of this project is to understand the causal relationship between altered excitability of striatal principal neurons called medium spiny neurons (MSN) and motivational deficits. Specifically, the project proposes to take advantage of a genetic mouse model of dopamine D2 receptor up-regulation in MSNs that is associated with a deficit in motivation. The main hypothesis of the application is that increased density of D2Rs in the striatum leads to motivational deficits by increasing the excitability of one class of MSNs, the striato-pallidal neurons. Two specific aims will address this hypothesis: Aim 1: To test the hypothesis that D2R up-regulation increases MSN excitability Aim 2: To test the hypothesis that MSN excitability is a key regulator of motivational behavior. The specific aims will be completed by combining mouse genetics with behavioral and electrophysiological studies. MSN excitability will be altered selectively in the striato-pallidal pathway of the striatum using virally mediated expression of ion channels. PUBLIC HEALTH RELEVANCE: Motivational abnormalities are core deficits in several mental disorders, but the underlying molecular mechanisms and the changes in neuronal function and circuitry have still to be identified. Studying whether altered excitability of striatal neurons leads to motivational impairments will help to understand the neuronal mechanisms that underlie motivation and could guide the development of new medication for psychiatric diseases.